title: Guanine holes are prominent targets for mutation in cancer and inherited disease.
abstract: Single base substitutions constitute the most frequent type of human gene mutation and are a leading cause of cancer and inherited disease. These alterations occur non-randomly in DNA, being strongly influenced by the local nucleotide sequence context. However, the molecular mechanisms underlying such sequence context-dependent mutagenesis are not fully understood. Using bioinformatics, computational and molecular modeling analyses, we have determined the frequencies of mutation at G • C bp in the context of all 64 5'-NGNN-3' motifs that contain the mutation at the second position. Twenty-four datasets were employed, comprising >530,000 somatic single base substitutions from 21 cancer genomes, >77,000 germline single-base substitutions causing or associated with human inherited disease and 16.7 million benign germline single-nucleotide variants. In several cancer types, the number of mutated motifs correlated both with the free energies of base stacking and the energies required for abstracting an electron from the target guanines (ionization potentials). Similar correlations were also evident for the pathological missense and nonsense germline mutations, but only when the target guanines were located on the non-transcribed DNA strand. Likewise, pathogenic splicing mutations predominantly affected positions in which a purine was located on the non-transcribed DNA strand. Novel candidate driver mutations and tissue-specific mutational patterns were also identified in the cancer datasets. We conclude that electron transfer reactions within the DNA molecule contribute to sequence context-dependent mutagenesis, involving both somatic driver and passenger mutations in cancer, as well as germline alterations causing or associated with inherited disease.
authors.affiliation: Division of Pharmacology and Toxicology, The University of Texas at Austin, Dell Pediatric Research Institute, Austin, Texas, United States of America ; Advanced Biomedical Computing Center, SAIC-Frederick, Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, United States of America.
authors.forename: Albino
authors.initials: A
authors.lastname: Bacolla
authors.forename: Nuri A
authors.initials: NA
authors.lastname: Temiz
authors.forename: Ming
authors.initials: M
authors.lastname: Yi
authors.forename: Joseph
authors.initials: J
authors.lastname: Ivanic
authors.forename: Regina Z
authors.initials: RZ
authors.lastname: Cer
authors.forename: Duncan E
authors.initials: DE
authors.lastname: Donohue
authors.forename: Edward V
authors.initials: EV
authors.lastname: Ball
authors.forename: Uma S
authors.initials: US
authors.lastname: Mudunuri
authors.forename: Guliang
authors.initials: G
authors.lastname: Wang
authors.forename: Aklank
authors.initials: A
authors.lastname: Jain
authors.forename: Natalia
authors.initials: N
authors.lastname: Volfovsky
authors.forename: Brian T
authors.initials: BT
authors.lastname: Luke
authors.forename: Robert M
authors.initials: RM
authors.lastname: Stephens
authors.forename: David N
authors.initials: DN
authors.lastname: Cooper
authors.forename: Jack R
authors.initials: JR
authors.lastname: Collins
authors.forename: Karen M
authors.initials: KM
authors.lastname: Vasquez
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics*; D019295:Computational Biology; D004273:DNA, Neoplasm / Q000235:genetics; D030342:Genetic Diseases, Inborn / Q000235:genetics* / Q000473:pathology; D018095:Germ-Line Mutation; D006147:Guanine; D006801:Humans; D008958:Models, Molecular; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology; D059372:Nucleotide Motifs / Q000235:genetics
chemical_list: D004273:DNA, Neoplasm; D006147:Guanine